2. Academic Validation
  3. Design, Synthesis, and Antirheumatoid Arthritis Mechanism of TLR4 Inhibitors

Design, Synthesis, and Antirheumatoid Arthritis Mechanism of TLR4 Inhibitors

  • ACS Omega. 2024 Aug 14;9(34):36232-36241. doi: 10.1021/acsomega.4c02344.
Shiyang Zhou 1 2 3 4 5,  Weiwei Xue 5,  Jun Tan 2
Affiliations

Affiliations

  • 1 Chongqing Chemical Industry Vocational College, Chongqing 401228, China.
  • 2 School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing 400067, China.
  • 3 Chongqing Academy of Traditional Chinese Medicine, Chongqing 400065, China.
  • 4 Key Laboratory of Tropical Medicinal Plant Chemistry of Hainan Province, Hainan Normal University, Haikou 571158, China.
  • 5 School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China.
PMID: 39220494 DOI: 10.1021/acsomega.4c02344
Abstract

A total of 12 carbonyl compounds were synthesized, their lipopolysaccharide induced inhibition, and activity of RAW264.7 cells was evaluated. The most active compound 3k inhibited RAW264.7 cells with IC50 value of 1.02 ± 0.08 μM. Compound 3k significantly inhibited the release of TNF-α, IL-1β, and IL-6 in supernatant for RAW264.7 cells. In vivo collagen-induced arthritis model tests administered orally, compound 3k showed effects similar to those of methotrexate in the positive control group. The preliminary mechanism study showed that compound 3k had an effect on abnormal expression for TLR4, TNF-α, NF-κB protein, and genes related to inflammation signaling pathway in RAW264.7 cells. Meanwhile, compound 3k showed a good affinity for the TLR4 receptor in molecular docking simulation. Therefore, compound 3k may be a promising lead compound for the treatment of rheumatoid arthritis.

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